Pandemic Potential? How Mutant Bird Flu Goes Airborne

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Half a year after controversy arose over research that created
more transmissible forms of the bird flu virus, the second and
final study to do so has been published. The publication
describes how the H5N1 virus, with a handful of genetic changes,
can become capable of airborne transmission — a prerequisite for
a global flu pandemic.

"It's our hope that tomorrow's publication will help to make the
world safer, particularly by stimulating many more scientists and
policymakers to focus on preparing defenses," Bruce Alberts,
editor-in-chief of the journal Science, where
the most recent H5N1 study appears, said during a press
conference Wednesday (June 20).

This study, conducted in Ron Fouchier’s lab at the Erasmus
Medical Center in the Netherlands, found that as few as five
mutations in the H5N1 virus were sufficient to enable it to
spread via airborne droplets between ferrets, the mammalian
stand-in for humans. Independently, another project accomplished
the same thing, but used a different technique to create the
mutant virus. [ 10
Deadly Diseases That Hopped Across Species ]

Both projects were intended to understand how H5N1 might acquire
the ability to start a pandemic among humans. (H5N1 has
devastated poultry around the world, but only rarely infects
humans. When it does infect humans, the virus cannot spread
effectively among them.)

In December, the U.S. National Science Advisory Board for
Biosecurity (NSABB) requested that
details of the studies be withheld to prevent them from
falling into the wrong hands. This request ignited concerns about
scientific censorship.

Some details of the study conducted in Fouchier's lab at Erasmus
Medical Center had already been made public when the controversy
erupted. However, the publication of the full study this week
reveals the mutant H5N1 viruses created by this research were not
as deadly as was widely reported. In fact, the researchers
report, the infection did not kill any of the ferrets that
contracted the disease through airborne droplets.

It was only when the researchers introduced massive doses of the
virus directly into the animals' bodies, in particular by putting
massive doses into their tracheae, that the infection killed.
However, "inoculations at such high doses do not represent the
natural route of infection," write the researchers.

According to the World Health Organization, nearly 60 percent of
human H5N1 cases have been fatal. However, some researchers have
said
this statistic is misleading, because only people sick enough
to see a doctor and receive a lab test are included in the
overall tally of about 600 cases.

Pandemic potential?

To figure out
how H5N1 might start a pandemic by acquiring the ability to
pass between people via airborne droplets, Fouchier and his
colleagues first looked to the past, specifically the flu
pandemics of 1918, 1957 and 1968.

The researchers introduced three key mutations associated with
pandemics into H5N1. This, however, was not enough to enable the
virus to spread via airborne droplets. So, the researchers let
nature take over, infecting ferrets with viruses taken from other
infected ferrets. After 10 cycles, or serial passages, they found
that the infection could spread via airflow from an infected
ferret to a healthy one housed in cage nearby.

The ferrets that contracted the altered H5N1 viruses this way
showed symptoms, including lethargy and lost appetites, but none
died during the experiment, the researchers write.

To figure out what made the altered H5N1 virus capable of air
travel, the researchers sequenced the genetic code of all of the
viruses capable of spreading this way and found the three
original mutations plus two additional changes shared by all of
them.

"We show that as little asfive mutations, but certainly less than
10, are sufficient to make H5N1 virus airborne," Fouchier said
during the press conference.

Studying influenza in ferrets is not the same as studying it in
humans. However, influenza viruses in ferrets cause a disease
similar to human flu, and ferrets are considered the best models
in which to study influenza viruses, Fouchier said.

More than one way to make airborne H5N1

The other H5N1 study, conducted by Yoshihiro Kawaoka, a professor
of virology at the University of Wisconsin-Madison, was published
in the journal Nature in May.

Kawaoka's team
took a different approach to the same end. They made an
airborne version of the virus by introducing four mutations into
its hemagglutinin protein (represented by the H in H5N1) and
using that to create a hybrid with the pandemic "swine flu"
virus, H1N1. Ferrets infected by airborne droplets carrying the
virus did not die in this experiment, either.

Preliminary word of these research projects stoked fear that
details on how to create these altered H5N1 viruses could fall
into the hands of terrorists or inept laboratories, resulting in
the release of a deadly virus that could spread around the globe.

At a conference in February, scientists and public health
officials
decided the studies should be published in full after a delay
and a moratorium on this and related research to allow time to
educate the public and alleviate anxieties. At the end of March,
NSABB reviewed revised versions of both papers, and a majority of
members recommended that Kawaoka's study be published as it was,
but recommended further revision for Fouchier's manuscript.

Ultimately, the details on the methods or results of this study
were not changed, Fouchier said. Instead, in agreement with NSABB
advice, Fouchier and colleagues added text to better explain the
goals, benefits to public health, biosafety
oversight and other details, he said in a statement.